Technical Field
The present invention relates to a medicament for suppressing rejection after corneal transplantation.
Related Art
Corneal transplantation is the most common organ transplantation performed about 2000 cases annually in Japan and about 40000 cases annually in the United States. In the case of standard corneal transplantation, its graft survival rate is considered to be 90% or higher. However, it has become a problem that rejection occurs in 40 to 90% of high-risk corneas such as corneas with angiogenesis, infection, autoimmune disease, or corneas that require regrafting. Nowadays, the incidence of acute rejection has reduced due to the use of immunosuppressants such as steroid and cyclosporine, and therefore the results of high-risk corneal transplantation have improved. In fact, however, there are still many problems that such immunosuppressants have side effects (e.g., infection, drug toxicity) and are ineffective for chronic rejection. Further, the number of donor corneas is not necessarily sufficient in Japan, and therefore it is clinically important to establish long-term immune tolerance of a transplanted organ (which is a state in which a transplanted organ satisfactorily functions even after discontinuation of administering an immunosuppressant).
As for immune tolerance, regulatory T cells (Tregs) have attracted attention which act to suppress immune responses. It has become clear that in corneal transplantation, reduced expression of Foxp3, which is a gene essential for the differentiation of Tregs, has an influence on rejection because it causes a reduction in the ability to suppress effector T cells that play a major role in rejection, and a reduction in suppressive cytokines (Chauhan S, et al., J Immunol., 182, 148-153 (2009)). It is also known that the survival of a corneal graft is prolonged by amplification of Tregs through administration of low-dose IL-2 (Tahvildari M et al., Transplantation, 100, 525-532 (2016)).
Rho kinase (Rho-associated, coiled-coil containing protein kinase: ROCK) is a serine-threonine kinase having a molecular weight of about 160 kDa, and its gene is preserved widely from lower animals such as nematodes and drosophila to humans. Rho kinase is involved in physiological functions such as cell morphological control, migration, and gene expression control as well as contraction of smooth muscle cells, and Rho kinase inhibitors have been developed as drugs for treatment of cardiovascular diseases etc.
Further, in recent years, Rho kinase inhibitors have been developed also as drugs for topical administration for treatment of ocular diseases such as glaucoma. As a medicament for the treatment of glaucoma/ocular hypertension, “GLANATEC (registered trademark) ophthalmic solution 0.4%” is commercially available which contains, as an active ingredient, ripasudil hydrochloride hydrate (4-fluoro-5-{[(2S)-2-methyl-1,4-diazepan-1-yl]sulfonyl}isoquinoline monohydrochloride dihydrate).
It is known that ripasudil is effective for the treatment of glaucoma/ocular hypertension, and is, in addition, useful for the treatment of ocular fundus diseases (Japanese Patent No. 5557408), for corneal thickness adjustment (WO 2016/047647), and for the prevention and treatment of complications after cataract surgery (JP 2017-61440 A). However, the effects of ripasudil on rejection after corneal transplant are unknown.